Acetate as a Mediator of Hematopoietic Stem Cell Inflammatory Response and Clonal Hematopoiesis

乙酸作为造血干细胞炎症反应和克隆造血的介质

• 批准号: 10464508
• 负责人: JONATHAN TIESSEN
• 金额: $ 4.68万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464508
• 关键词: ATP Citrate (pro-S)-Lyase; Acetate-CoA Ligase; Acetates; Acetyl Coenzyme A; Adult; Bacterial Infections; Biological Assay; Bolus Infusion; Cells; Cellular biology; ChIP-seq; Chronic; Citrates; Consumption; Cues; Data; Diet; Dietary Component; Disease; Fructose; Gene Expression; Gene Expression Profiling; Genes; Genetic; Goals; Health; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Histone Acetylation; Human; Immune; Immune response; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interferons; Interleukins; Link; Lipopolysaccharides; Literature; Maintenance; Measures; Mediator of activation protein; Metabolic; Metabolism; Modeling; Mus; Mutant Strains Mice; Mutation; Natural regeneration; Phenotype; Production; Proteomics; Public Health; Publishing; Role; Serum; Signal Transduction; Source; Stimulus; Supplementation; Testing; Transplantation; Work; base; cell behavior; cytokine; dietary; epigenetic profiling; epigenetic regulation; immune function; mouse model; mutant; novel; response; single molecule; stem cell function; stem cells; systemic inflammatory response; transcriptome sequencing

PROJECT SUMMARY Hematopoietic stem and progenitor cells (HSPCs) are responsible for the maintenance and regeneration of the adult hematopoietic system. These cells are responsive to systemic cues that influence their differentiation, such as inflammation, in the form of cytokines such as interferons and interleukins. Inflammation is particularly noteworthy for its influence not only in normal hematopoiesis, but as a driver of clonal hematopoiesis (CH), the overrepresentation of specific mutant clones in the hematopoietic system. Mutations in Tet2 represent a common driver of CH, and Tet2 mutant HSPCs expand preferentially in response to inflammatory stimuli. Recently, acetate has been implicated as an inflammation-associated metabolic signal. Acetate rises systemically during inflammation but is also elevated as a byproduct of dietary components, particularly fructose. I have found in preliminary studies that supplementing acetate, either directly or through fructose, along with inflammatory stimuli broadly exacerbates inflammation in the form of inflammatory serum cytokines and HSPC inflammatory gene expression. Together, these results suggest a role for acetate as a diet-associated metabolic mediator of inflammation, relevant to both normal and clonal hematopoiesis. Therefore, the focus of this proposal is to 1) interrogate the hematopoietic response to changes in systemic acetate levels during inflammation and to 2) interrogate acetate as a driver of clonal hematopoiesis during inflammation. These aims will be accomplished through a combination of functional, gene expression, and phenotypic studies of HSPCs in response to acetate during inflammation.

项目概要 造血干细胞和祖细胞 (HSPC) 负责造血干细胞和祖细胞的维持和再生 成人造血系统。这些细胞对影响其分化的系统信号做出反应，例如 作为炎症，以细胞因子的形式存在，例如干扰素和白细胞介素。炎症特别严重 值得注意的是，它不仅影响正常造血，而且作为克隆造血 (CH) 的驱动因素， 造血系统中特定突变克隆的过度表达。 Tet2 中的突变代表了一种常见的 CH 的驱动因素和 Tet2 突变体 HSPC 会优先扩增以响应炎症刺激。最近， 乙酸盐被认为是一种与炎症相关的代谢信号。醋酸盐在期间系统性上升 炎症，但作为饮食成分（尤其是果糖）的副产品也会升高。我发现在 初步研究表明直接或通过果糖补充醋酸盐以及炎症刺激 以炎症血清细胞因子和 HSPC 炎症基因的形式广泛加剧炎症 表达。总之，这些结果表明乙酸盐作为与饮食相关的代谢介质的作用 炎症，与正常和克隆造血有关。因此，本提案的重点是1） 询问造血系统对炎症期间全身醋酸盐水平变化的反应以及 2) 探究乙酸盐作为炎症期间克隆造血的驱动因素。这些目标将会实现 通过结合 HSPC 对醋酸盐的功能、基因表达和表型研究 炎症期间。